US 7,491,827 B2
Aryl sulfonamides useful as inhibitors of chemokine receptor activity
Mingshi Dai, Billerica, Mass. (US); Bing Guan, Needham, Mass. (US); Robert A. Bennett, Milford, Mass. (US); Douglas F. Burdi, Arlington, Mass. (US); Shomir Ghosh, Brookline, Mass. (US); Gang Li, Westborough, Mass. (US); Charles Minor, Kingston, Mass. (US); and Tracy J. Jenkins, Belmont, Mass. (US)
Assigned to Millennium Pharmaceuticals, Inc., Cambridge, Mass. (US)
Filed on Jul. 14, 2004, as Appl. No. 10/891,362.
Application 10/891362 is a continuation in part of application No. 10/744236, filed on Dec. 23, 2003, granted, now 7,329,755.
Application 10/744236 is a continuation in part of application No. 10/744585, filed on Dec. 23, 2003, granted, now 7,378,525.
Prior Publication US 2005/0085518 A1, Apr. 21, 2005
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 211/06 (2006.01); C07D 215/38 (2006.01); C07D 413/00 (2006.01); C07D 239/02 (2006.01)
U.S. Cl. 546—206  [546/158; 546/169; 544/129; 544/298] 32 Claims
 
1. A compound represented by structural formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein:
X1 is a covalent bond, C═Z is C═O, X is a bond, m is 0, and n is 2, or
X1 is C═O, C═Z is absent, X is a bond, m is 0, and n is 2;
Ar in Formula (1) is selected from:

OG Complex Work Unit Drawing
R1 is a substituted or unsubstituted aromatic or carbocyclic ring;
R2 is —H or a C1-C3 alkyl group;
R3 is —H;
R4 is a substituted or unsubstituted piperidinyl group;
Ar is optionally substituted at any substitutable carbon or nitrogen atom with p independent occurrences of R6, wherein:
p is 0, 1, 2, or 3; and
each occurrence of R6 is independently halogen, —CN, NO2, —R7, or —OR7, wherein each occurrence of R7 is independently hydrogen or a substituted or unsubstituted C1-C6aliphatic group;
wherein:
a) R1 is optionally substituted at one or more substitutable aromatic or non-aromatic carbon atoms with q occurrences of R8, wherein:
q is 0, 1, 2, or 3,
each occurrence of R8 is independently halogen, —R10, —OR10, —SR10, —NO2, —CN, —N(R11)2, —NR11CO2R10, —NR11C(O)R10, —NR11NR11C(O)R10, —N(R11)C(O)N(R11)2, —NR11NR11C(O)N(R11)2, —NR11NR11CO2R10, —C(O)C(O)R10, —C(O)CH2C(O)R10, —CO2R10, —C(O)R10, —C(O)N(R11)2, —OC(O)R10, —OC(O)N(R11)2, —S(O)2R10, —SO2N(R11)2, —S(O)R10, —NR11SO2N(R11)2, —NR11SO2R10, —C(═S)N(R11)2, —C(═NH)—N(R11)2, -V-R10, -V-OH, -V-OR10, -V-SH, -V-SR10, -V-NO2, -V-CN, -V-N(R11)2, -V-NR11CO2R10, -V-NR11C(O)R10, -V-NR11NR11C(O)R10, -V-N(R11)C(O)N(R11)2, -V-NR11NR11C(O)N(R11)2, -V-NR11NR11CO2R10, -V-C(O)C(O)R10, -V-C(O)CH2C(O)R10, -V-CO2R10, -V-C(O)R10, -V-C(O)N(R102, -V-OC(O)R10, -V-OC(O)N(R11)2, -V-S(O)2R10, -V-SO2N(R11)2, -V-S(O)R10, -V-NR11SO2N(R11)2, -V-NR11SO2R10, -V-C(═S)N(R11)2or -V-C(═NH)—N(R11)2, or two occurrences of R8, taken together with the atom(s) to which they are bound form a substituted or unsubstituted cycloaliphatic or substituted or unsubstituted non-aromatic heterocyclic ring, and when R1 is a non-aromatic ring, any occurrence of R8 is also selected from: ═O, ═S, ═NNHR*, ═NN(R*)2, ═NNHC(O)R*, ═NNHCO2(alkyl), ═NNHSO2 (alkyl), or ═NR*;
V is a substituted or unsubstitutdd C1-C6alkylene group;
each occurrence of R10 is independently hydrogen or a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloaliphatic ring, a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted aromatic ring;
each occurrence of R11 is independently —R10, —CO2R10, —SO2R10 or —C(O)R10, or two occurrences of R11, taken together with the nitrogen atom to which they are bound form a substituted or unsubstituted non-aromatic heterocyclic ring;
each occurrence of R* is independently hydrogen, or a substituted or unsubstituted aliphatic group;
b) R4 is optionally and independently substituted at one or more substitutable non-aromatic carbon atoms with s occurrences of R13, and at one or more substitutable nitrogen atoms with r occurrences of R14 wherein:
s is 0, 1, 2, or 3,
r is 0 or 1,
provided that the sum of s and r is not greater than 4,
each occurrence of R13 is independently halogen, —R15, —OR15, —SR15, —NO2, —CN, —N(R16)2, —NR16CO2R15, —NR16C(O)R15, —NR16NR16C(O)R15, —N(R15)C(O)N(R16)2, NR16NR16C(O)N(R16)2, —NR16NR16CO2R15, —C(O)C(O)R15, —C(O)CH2C(O)R15, —CO2R15, —C(O)R15, —C(O)N(R162, —OC(O)R15, —OC(O)N(R162, —S(O)2R15, —SO2N(R16)2, —S(O)R15, —NR16SO2N(R16)2, —NR16SO2R15, —C(═S)N(R16)2, —C(═NH)—N(R16)2, -W-R15, -W-OH, -W-OR15, -W-SH, -W-SR15, -W-NO2, -W-CN, -W-N(R16)2, -W-NR16CO2R15, -W-NR16C(O)R15, -W-NR16NR16C(O)R15, -W-N(R16)C(O)N(R16)2, -W-NR16NR16C(O)N(R16)2, -W-NR16NR16CO2R15, -W-C(O)C(O)R15, -W-C(O)CH2C(O)R15, -W-CO2R15, -W-C(O)R15, -W-C(O)N(R16)2, -W-OC(O)R15, -W-OC(O)N(R16)2, -W-S(O)2R15, -W-SO2N(R16)2, -W-S(O)R15, -W-NR16SO2N(R16)2, -W-NR16SO2R15, -W-C(═S)N(R16)2, or -W-C(═NH)—N(R16)2, or two occurrences of R13, taken together with the atom(s) to which they are bound form a substituted or unsubstituted cycloaliphatic or substituted or unsubstituted non-aromatic heterocyclic ring, and when R4 is anon-aromatic ring, any occurrence of R13 is also selected from: ═O, ═S, ═NNHR+, ═NN(R+)2, ═NNHC(O)R+, ═NNHCO2(alkyl), ═NNHSO2 (alkyl), or ═NR+;
W is a substituted or unsubstituted C1-C6alkylene group;
each occurrence of R15 is independently hydrogen or substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloaliphatic, a substituted or unsubstituted non-aromatic heterocyclic ring or a substituted or unsubstituted aromatic ring,
each occurrence of R16 is independently R15, —CO2R15, —SO2R15 or —C(O)R15, or two occurrences of R16, taken together with the nitrogen atom, form a substituted or unsubstituted non-aromatic heterocyclic ring;
each occurrence of R+ is independently hydrogen, or a substituted or unsubstituted aliphatic group; and
each occurrence of R14 is independently —R17, -L-N(R17)2, —C(O)R17, —C(O)-L-R17, -L-C(O)R7, —CO2R17, -L-CO2R17, —C(O)C(O)R17, -L-C(O)C(O)R17, —C(O)-L-C(O)R17, —SO2R17, L-SO2R17, —SO2N(R17)2, -L-SO2N(R17)2, —C(═S)N(R17)2, —C(═NH)—N(R17)2, L-NR17SO2R17, —C(O)—N(R17)2, -L-C(O)—N(R17)2, —C(O)-L-N(R17)2 or —C(O)-L-OR17;
wherein L is a substituted or unsubstituted C1-C6alkylene group; and
each occurrence of R17 is independently hydrogen, a substituted or unsubstituted group selected from an aliphatic, aromatic, cycloaliphatic, or non-aromatic heterocyclic group, or two occurrences of R17, taken together with the nitrogen atom, form a substituted or unsubstituted non-aromatic heterocyclic ring.